Leydig Cell Tumour of the Testis

Leydig cell tumour is the commonest sex cord stromal tumour of the testis, making up about 1 to 3% of testicular tumours. It arises from the testosterone producing Leydig cells.

It has two peaks: boys aged 5 to 10 years and men aged 30 to 60 years. About 90% are benign, and about 10% are malignant. Adults have a higher rate of malignancy than children, where nearly all are benign.

Pathophysiology. Most tumours secrete testosterone, and also oestradiol through aromatisation. The result in children is early virilisation, and in adults gynaecomastia and sexual dysfunction.

Features that raise concern for malignancy:

• Size over 5 cm, age over 50, infiltrative margins, necrosis and vascular invasion.
• Nuclear atypia, over 3 mitoses in 10 high power fields, and extension beyond the testis.
• DNA aneuploidy and high proliferation index.

Associations: Klinefelter syndrome, Leydig cell hyperplasia, fumarate hydratase mutations, and rarely congenital adrenal hyperplasia (where adrenal rest tumours mimic it).

Boys: isosexual precocious puberty with enlarged penis, pubic hair, deep voice, acne and rapid growth with advanced bone age. The tumour bearing testis is enlarged and the other testis is prepubertal in size.

Adults: painless testicular swelling or an incidental mass, gynaecomastia in about 10 to 30%, reduced libido, erectile dysfunction and infertility. A firm, small nodule under 3 cm is typical. About 5% are bilateral.

• Scrotal ultrasound: a well circumscribed, small, hypoechoic, hypervascular nodule, often under 3 cm.
• MRI of the scrotum when ultrasound is equivocal.
• Hormones: total testosterone (raised in many), oestradiol (raised), LH and FSH (suppressed), inhibin B, 17-hydroxyprogesterone, and androstenedione. In children, check 17-hydroxyprogesterone and DHEA sulphate to exclude adrenal sources, and consider LH after stimulation to exclude central puberty.
• AFP, beta-hCG and lactate dehydrogenase to exclude germ cell tumour.
• CT of chest, abdomen and pelvis when malignant features are present.
• Frozen section at exploration helps decide between enucleation and orchidectomy. Histology: polygonal cells with eosinophilic cytoplasm and Reinke crystals in some. Immunostaining is positive for inhibin, calretinin, melan-A and SF-1, and negative for OCT3/4 and placental alkaline phosphatase.

Differential diagnosis.

• Testicular adrenal rest tumour
• Seminoma and other germ cell tumours
• Sertoli cell tumour
• Large cell calcifying Sertoli cell tumour
• Leydig cell hyperplasia
• Testicular lymphoma
• Malakoplakia or orchitis

• Adults with a mass: radical inguinal orchidectomy with high ligation of the cord, or testis sparing enucleation for small (under 2 cm), benign looking tumours with a normal contralateral testis, confirmed by frozen section. Orchidectomy for any malignant features.
• Children: testis sparing enucleation is preferred, since nearly all are benign, with frozen section to confirm.
• Sperm banking before surgery in men who want children.
• Malignant tumour:
  • Retroperitoneal lymph node dissection for limited nodal disease, since chemotherapy and radiotherapy have poor effect.
  • Cisplatin based chemotherapy has been tried with variable response. Treatment is in a specialist centre.
• After surgery: hormones normalise within weeks to months. Gynaecomastia may persist and needs surgery, or tamoxifen 20 mg orally daily for 3 to 6 months in early painful gynaecomastia.
• Hypogonadism after surgery: testosterone replacement with gel 50 mg daily or testosterone undecanoate 1000 mg intramuscularly every 10 to 14 weeks after loading, titrated to a mid-normal level.
• Boys with premature puberty may develop central precocious puberty after tumour removal, and need a GnRH analogue under paediatric endocrinology.

Monitoring. Benign tumour: testosterone, oestradiol, LH and FSH at 6 weeks, 3 months and 12 months, and testicular ultrasound yearly. Malignant features: clinical review, markers and CT every 3 to 6 months for 2 years, then yearly for at least 5 years. Bone density in prolonged hypogonadism.

Referral and escalation. Refer to urology, with paediatric endocrinology for children. Urgent referral for a palpable mass, metastasis or rapid growth.